We performed a retrospective study in 185 patients with myelogenous leukemias who had received hematopoietic cells from unrelated donors. The aim of this study was to answer the question wether the benefit of KIR ligand incompatibility seen in haploidentical tranplantations can also be seen using unrelated donors. We could not detect a significant difference in survival between patients with a KIR ligand incompatibility and those with either fully matched or partially mismatched unrelated donors in this patient cohort. / In der Therapie von Leukämien ist die Knochenmark- bzw. Stammzelltransplantation eine tragende Säule. Für den Transplantationserfolg ist eine Übereinstimmung der Haupthistokompatibilitätsantige (HLA-Antigene der Klassen I und II) zwischen Spender und Empfänger von zentraler Bedeutung. Diese Notwendigkeit ergibt sich aus der sogenannten MHC-Restriktion in der T-Zellrezeptorerkennung. Ob auch NK-Zellrezeptoren und deren Liganden in der Spenderauswahl berücksichtigt werden sollten, ist bisher unzureichend untersucht. Insbesondere trifft das für die KIR-Rezeptoren zu, die wie die T-Zellrezeptoren ebenfalls HLA-Antigene als Liganden besitzen. Velardi et al. haben 2002 erstmalig gezeigt, daß in der Therapie myeloischer Leukämien die Transplantation von Blutstammzellen verwandter Spender mit KIR-Liganden-Inkompatibilität von klinischem Vorteil ist. Ob KIR-Liganden-Inkompatibilität auch bei Knochenmark-/ Stammzelltransplantationen Unverwandter Bedeutung erlangen könnte, war zu Studienbeginn offen und blieb auch infolge diskrepanter Untersuchungsergebnisse von verschiedenen Arbeitsgruppen im Verlauf der Studie widersprüchlich. Im Rahmen dieser Arbeit wurde diese Fragestellung, die auch Teil einer internationalen Studie war, an 185 Spender-Empfänger-Paaren retrospektiv untersucht. Dabei wurde bei den Paaren einerseits die KIR-Liganden-Kompatibilität auf der Grundlage der HLA-C-Supertypen erschlossen (nach Velardi et al.). Andererseits konnte sie im internationalen Studienprogramm direkt aus dem KIR-Genotyp des Spenders und dem HLA-C-Supertyp des Empfängers ermittelt werden. Die Untersuchungen ergaben folgende Resultate: bei Vorliegen von KIR-Liganden-Inkompatibilität hat die Verwendung von ATG als Bestandteil der GvHD-Prophylaxe keinen Einfluß auf das klinische Ergebnis. Die Vermutungen von Giebel et al. wurden damit nicht gestützt. Die Bestimmung des KIR-Liganden-Status mit Hilfe der Rückschlußmethode allein aus dem HLA-Typ ist unzuverlässig. Für eine exakte Differenzierung ist die gleichzeitige KIR-Genotypisierung erforderlich. KIR-Liganden-Inkompatibilität ist bei unverwandten Knochenmark-/ Stammzelltransplantationen nicht von klinischem Vorteil. Auch ein gezieltes Aussuchen HLA-C-inkompatibler Spender auf der Grundlage einer KIR-Genotypisierung stellt derzeit keine therapeutische Option dar.

In this study, we aimed to determine the levels of cytokines IL-1β, IL-4, IL-10, IFN-γ, MIF and VEGF in tears derived from healthy subjects. We tested cytokines as potential markers of inflammation for their potential use in clinical practice. Having reliable method for measuring cytokine levels in tears would enable an early diagnosis of eye diseases. In two phases, cytokines in tears of healthy individuals were analyzed using Bio-Plex Cytokine Assay (Bio-Rad). We assessed the suitability of methods for diagnostic purposes as well as the suitability of our selected cytokines. Statistically significant positive correlations of cytokines were confirmed: IL-10 with IFN-γ (r = 0,81), MIF with VEGF (r = 0,42 / r = 0,49), IL-1β with IL-10 (r = 0,52), IL-1β with IFN-γ (r = 0,55), IL-1β with VEGF (r = 0,38), IFN-γ with VEGF (r = 0,45) and IL-4 with VEGF (r = 0,48) in healthy subjects in tears. IL-4 (r = -0,37) and IFN-γ (r = -0,42) correlate negatively with age. In healthy individuals, there seem to be no differences with regard to gender, BMI, body fat, time of meal consumption prior to tear collection, eye strain when using a computer, dry eyes. Thus, studied cytokines are suitable for diagnostic purposes. Significant differences in concentrations of four (IL-1β, IL-10, IFN-γ a VEGF) of the five...

Submitted by Johnny Rodrigues (johnnyrodrigues@ufcg.edu.br) on 2018-05-04T22:06:03Z No. of bitstreams: 1 HELDER FERNANDO DE ARAÚJO OLIVEIRA - TESE PPGCC 2015..pdf: 1535968 bytes, checksum: ea0ac08d16d7773542f5d7193c85c162 (MD5) / Made available in DSpace on 2018-05-04T22:06:03Z (GMT). No. of bitstreams: 1 HELDER FERNANDO DE ARAÚJO OLIVEIRA - TESE PPGCC 2015..pdf: 1535968 bytes, checksum: ea0ac08d16d7773542f5d7193c85c162 (MD5) Previous issue date: 2015-11-10 / Capes / Consumo de energia é um grande desafio durante o projeto de um SoC (System-on-a-Chip). Dependendo do projeto, para garantir maior precisão na estimação do consumo de energia, pode ser necessário estimar o consumo de energia do sistema ou parte dele utilizando diferentes elementos: diferentes abordagens de estimação, ferramentas ou, até mesmo, modelos descritos em variadas linguagens e/ou níveis de abstração. Porém, consiste em um desafio incorporar tais elementos para criação de um ambiente de simulação distribuído e heterogêneo, o qual permita que estes se comuniquem e troquem informações de modo sincronizado. Diante do exposto, a presente pesquisa tem como objetivo desenvolver uma abordagem, utilizando-se High Level Architecture (HLA), a fim de permitir a criação de um ambiente de simulação distribuído e heterogêneo, composto por diferentes ferramentas e modelos. Estes modelos podem ser descritos em diversas linguagens e/ou níveis de abstração, como também podem utilizar diferentes abordagens a estimação do consumo de energia. O uso da HLA permite que os elementos que compõem este ambiente heterogêneo possam ser simulados de maneira sincronizada e distribuída. A abordagem deve proporcionar a coleta e o agrupamento de dados de estimação de consumo de energia de modo centralizado. Para realização dos estudos de caso, foi utilizado um benchmark composto por um conjunto escalável de MPSoC (MultiProcessor System-on-Chip) descrito em C++/SystemC e o arcabouço Ptolemy. Um projeto em SystemVerilog/Verilog também foi utilizado para validar a coleta de dados de estimação de consumo de energia de modelos descritos nessas linguagens, por meio da abordagem proposta. Resultados experimentais demonstraram a flexibilidade da abordagem e sua aplicabilidade para a criação de um ambiente de simulação síncrono e heterogêneo, o qual promove uma visão integrada dos dados de energia estimados. / Energy consumption is a big challenge in SoC (System-on-a-Chip) design. Depending on the project requirements, to guarantee a better accuracy in power estimation, it might be necessary to estimate the power consumption of a system or part of it using different elements: different power estimation approaches, tools or, even, models described in different languages and/or abstraction levels. However, it is a challenge to incorporate these elements to create a simulation environment distributed and heterogeneous, which allows these elements to communicate and exchange information synchronously. In view of what has been exposed, the present research aims to develop an approach using HLA (High Level Architecture), enabling the creation of an environment distributed and heterogeneous, composed by different tools and models. These models can be described in different languages and/or abstraction levels, as well as use different power estimation approaches. The use of HLA enables the synchronized and distributed simulation of the elements that compose the simulation environment. The approach must allow the collecting and grouping of power estimation data in a centralized manner. As a case study, it has been used a benchmark composed of a scalable set of MPSoCs (MultiProcessor Systemon-Chip) which is described in C++/SystemC and the Ptolemy framework. A project in SystemVerilog/Verilog was also used to validate the power estimation data collected from models described in these languages, through the proposed approach. The experimental results show the approach flexibility and its applicability on creation of a distributed and synchronous simulation environment, which promotes an integrated view of power estimation data.

Abstract The aims of this study were to investigate the clinical features, the endoscopic and histological abnormalities of ileocolonic and gastroduodenal mucosa and immunogenetic background of microscopic colitis (MC) and its subtypes collagenous colitis (CC) and lymphocytic colitis (LC). 30 patients with CC and 54 with LC were examined with different control groups used according to the study. The mean age at diagnosis was in the sixties in both CC and LC, with a female preponderance in both Autoimmune conditions such as celiac diseased (CD) were common in MC. Bronchial asthma associated with LC. Lactose intolerance associated with MC but colonic diverticulosis was rare. Ileal histological changes were common in MC. Focal gastritis did not associate with MC. Lymphocytic gastritis was found only in LC. Gastric endoscopic erosions were more prevalent in CC than in LC. The age at diagnosis of MC was higher in H. pylori positive than negative patients. The patients with MC had shorter duodenal villi than controls even when patients with CD were excluded. HLA-DR3-DQ2 haplotype and TNF2 allele carriage were more frequent in patients with MC compared to controls. The genotype GG of IL-6-174 was more prevalent in MC compared to the controls. IL-6 genotype did not associate with the serum IL-6 concentration. The concentration of IL-6 was higher in patients with CC than in LC. In conclusion, in addition to colonic typical inflammation, histological abnormalities were detected also in gastric, duodenal and ileal mucosa. CD was common in MC, but there was no association with specific types of gastritis. HLA association was found in MC. Polymorphism in the proinflammatory IL-6-174 gene displayed a possible association with MC. Although CC and LC share many clinical features, the differences in the occurrence of immune conditions, gastric abnormalities and IL-6 response point to differences in their pathogenesis. / Tiivistelmä Tutkimuksen tavoitteena oli tutkia mikroskooppisen koliitin sekä sen alaryhmien, kollageenikoliitin ja lymfosyyttisen koliitin kliinisiä piirteitä, mahalaukun ja ohutsuolen limakalvon muutoksia sekä immunogeneettistä taustaa. Tutkimukseen osallistui 30 kollageeni- ja 54 lymfosyyttikoliittipotilasta sekä verrokkeja. Sekä kollageenikoliitti että lymfosyyttinen koliitti diagnosoitiin keskimäärin 50–60 v iässä, ja molemmissa tautiryhmissä naisia oli enemmän kuin miehiä. Autoimmuunisairaudet kuten keliakia olivat yleisiä liitännäissairauksia. Astmaa esiintyi lymfosyyttistä koliittia sairastavilla verrokkeja enemmän. Laktoosi-intoleranssi oli yleistä, mutta paksusuolen divertikuloosia oli harvoin mikroskooppista koliittia sairastavilla potilailla. Ileumin muutokset olivat yleisiä. Mikroskooppinen koliitti ei assosioitunut fokaaliseen gastriittiin. Lymfosyyttigastriittia todettiin vain lymfosyyttisessä koliitissa. Mahalaukun eroosioita esiintyi enemmän kollageenikoliitissa kuin lymfosyyttisessa koliitissa. Mikroskooppinen koliitti ilmeni iäkkäämpänä niillä, joilla todettiin helikobakteeri. Pohjukaissuolen suolinukka oli keliakiasta riippumatta matalampaa kuin verrokeilla. HLA-DR3-DQ2 haplotyyppiä, TNF-2 alleelia ja IL-6-174-GG genotyyppiä esiintyi enemmmän mikroskooppista koliittia sairastavilla potilailla kuin verrokeilla. IL-6 genotyyppi ei vaikuttanut seerumin IL-6-pitoisuuteen. IL-6 pitoisuus oli korkeampi kollageenikoliitissa kuin lymfosyyttisessä koliitissa. Havainnot osoittavat, että mikroskooppisessa koliitissa limakalvomuutoksia on paksusuolen lisäksi myös muualla mahasuolikanavassa. Keliakia on tavallinen liitännäistauti. HLA-DR3-DQ2 on yleinen mikroskooppista koliittia sairastavilla myös ilman keliakiaa. IL-6-174-GG genotyypin yleisyys viittaa siihen, että tämä polymorfismi saattaa altistaa mikroskooppiselle koliitille. Vaikka kollageenikoliitti ja lymfosyyttinen koliitti ovat kliinisesti samankaltaisia sairauksia, erot tautiassosiaatioissa, mahan limakalvon muutoksissa ja seerumin IL-6-tasoissa viittaavat erilaisiin syntymekanismeihin.

Variation in the sequence of T cell epitopes between dengue virus (DENV) serotypes is believed to alter memory T cell responses during second heterologous infections contributing to pathology following DENV infection. We identified a highly conserved, novel, HLA-B57-restricted epitope on the DENV NS1 protein, NS126-34. We predicted higher frequencies of NS126-34-specific CD8+ T cells in PBMC from individuals undergoing secondary, rather than primary, DENV infection due to the expansion of memory CD8+T cells. We generated a tetramer against this epitope (B57-NS126-34TET) and used it to assess the frequencies and phenotype of antigen-specific T cells in samples from a clinical cohort of children with acute DENV infection established in Bangkok, Thailand. High tetramer-positive T cell frequencies during acute infection were seen in only 1 of 9 subjects with secondary infection. B57-NS126-34-specific, other DENV epitope-specific CD8+ T cells, as well as total CD8+ T cells, expressed an activated phenotype (CD69+ and/or CD38+) during acute infection. In contrast, expression of CD71 was largely limited to DENV-specific CD8+ T cells. In vitro stimulation of CD8+ T cell lines, generated against three different DENV epitopes, indicated that CD71 expression was differentially sensitive to stimulation by homologous and heterologous variant peptides with substantial upregulation of CD71 detected to peptides which also elicited strong functional responses. CD71 may therefore represent a useful marker of antigenspecific T cell activation. During the course of our analysis we found substantial binding of B57-NS126-34 TET to CD8- cells. We demonstrated that the B57-NS126-34 TET bound KIR3DL1, an inhibitory receptor on natural killer (NK) cells. NK sensitive target cells presenting the NS126-34 peptide in the context of HLA-B57 were able to dampen functional responses of only KIR3DL1+ NK cells. Analysis of the activation of an NK enriched population in our Thai cohort revealed peak activation during the critical time phase in patients with severe dengue illness, dengue hemorrhagic fever, compared to people with mild illness. Our data identified CD71 as biologically useful marker to study DENV-specific CD8+ T cell responses and highlighted the role of viral peptides in modulating NK cell activation through KIR-MHC class I interactions during DENV infection.

[ES] El cáncer de pulmón no microcítico (CPNM) representa un 80% de los casos de cáncer de pulmón, siendo uno de los tipos de cáncer más frecuentes y mortales. El tratamiento con inmunoterapia ha mejorado significativamente el pronóstico de los pacientes en las últimas décadas. No obstante, no todos los pacientes responden al tratamiento, por lo que se necesitan nuevos biomarcadores para predecir qué pacientes se podrían beneficiar de la inmunoterapia. El principal objetivo de esta tesis es obtener nuevos biomarcadores no invasivos para pacientes de CPNM avanzado tratados con inmunoterapia. Se incluyeron 52 pacientes de CPNM en estadios avanzados tratados con anti-PD1 o anti-PD1 en combinación con quimioterapia (anti-PD1+CT) en primera línea. Se analizaron biomarcadores no invasivos en muestras de sangre periférica, obtenidas antes del tratamiento y en la primera evaluación de respuesta. Los biomarcadores analizados en este estudio fueron: i) parámetros hematológicos e inmunológicos, ii) expresión de genes inmunoreguladores en células mononucleares de sangre periférica (PBMCs), iii) repertorio de TCR-ß y iv) genotipo de HLA. También se analizaron 13 controles sanos, y se observó que los pacientes con CPNM presentaron menores niveles de expresión de genes relacionados con las células T. Además, los pacientes con CPNM tenían menor número de clones de TCR-ß. Se analizó el valor predictivo y pronóstico de los potenciales biomarcadores independientemente en pacientes tratados con anti-PD1 o anti-PD+CT. Se encontraron biomarcadores con valor pronóstico, bien en las muestras basales o en las muestras tomadas en la primera evaluación de respuesta. Al utilizar muestras no invasivas, también se pudo estudiar la dinámica de los biomarcadores a lo largo del tratamiento, observando que algunos cambios ocurrían de manera diferencial en pacientes respondedores o dependiendo del tratamiento. La integración de los datos de las variables analizadas ha resultado en una propuesta de un modelo multivariante capaz de predecir qué pacientes tendrán mejor pronóstico, en el subgrupo de pacientes tratados con anti-PD1. Además, se crearon dos inmunogramas no invasivos incluyendo los ratios de los biomarcadores entre muestras tomadas antes y durante el tratamiento. Estos modelos se realizaron específicamente para cada tipo de tratamiento, y podrían ser útiles para monitorizar la respuesta durante el tratamiento. Este estudio resalta el papel de la biopsia líquida como una herramienta no invasiva para analizar biomarcadores de forma integral que permiten caracterizar y monitorizar el estatus inmune en pacientes con CPNM tratados con inmunoterapia o quimioinmunoterapia. / [CA] El càncer de pulmó no microcític (CPNM) representa un 80% dels casos de càncer de pulmó, i és un dels tipus de càncer més freqüents i mortals. El tractament amb immunoteràpia ha millorat significativament el pronòstic dels pacients en les últimes dècades. Malgrat això, no tots el pacients responen, per la qual cosa es necessiten nous biomarcadors per predir què pacients es beneficiaran del tractament amb immunoteràpia. El principal objectiu d'aquesta tesi és obtindre nous biomarcadors no invasius per a pacients de CPNM avançat tractats amb immunoteràpia. Es van incloure 52 pacients de CPNM en estadis avançats tractats amb anti-PD1 o anti-PD1 en combinació amb quimioteràpia (anti-PD1+CT) en primera línia. Es van analitzar biomarcadors no invasius a partir de mostres de sang perifèrica, que es van obtindre abans del tractament i en la primera avaluació de resposta. Els potencials biomarcadors analitzats en aquest estudi van ser: i) paràmetres hematològics i immunològics, ii) expressió de gens immunoreguladors en cèl·lules mononuclears de sang perifèrica (PBMCs), iii) repertori de TCR-ß i iv) genotip d'HLA. També es van analitzar 13 controls sans, i es va observar que els pacients amb CPNM presentaven menors nivells d'expressió de gens relacionats amb les cèl·lules T. A més, els pacients amb CPNM tenien menor riquesa de repertori de TCR-ß. S'han analitzat el valor predictiu i pronòstic dels potencials biomarcadors independentment en pacients tractats amb anti-PD1 o anti-PD1+CT. S'han trobat biomarcadors amb valor pronòstic, bé en les mostres basals o en les mostres preses en la primera avaluació de resposta. Com s'han utilitzat mostres no invasives, també s'ha pogut analitzar la dinàmica dels biomarcadores al llarg del tractament, i s'han observat canvis específics de pacients responedors o del tipus de tractament. La integració de les variables analitzades ha resultat en una proposta d'un model multivariant capaç de predir quins pacients amb CPNM tindran millor pronòstic, en el subgrup de pacients tractats amb anti-PD1. També s'han fet dos immunograms no invasius incloent els ràtios dels biomarcadors entre mostres preses abans i durant el tractament. Aquests models son específics per a cada tipus de tractament, i podrien ser útils per a monitorar la resposta durant el tractament. Aquest estudi ressalta el paper de la biòpsia líquida com una eina no invasiva per a analitzar biomarcadors de forma integral que permeten caracteritzar i monitorar l'estatus immune en pacients amb CPNM tractats amb immunoteràpia o quimioimmunoteràpia. / [EN] Non-Small Cell Lung Cancer (NSCLC) represents 80% of lung cancer cases, being one of the most frequent and death causing cancers. Recently developed treatments with immunotherapy have improved patient prognosis. However, a significant number of patients do not respond to treatment, thus there is an urgent need for biomarkers to predict which patients will benefit from immunotherapy. The main objective of this thesis was to obtain novel non-invasive biomarkers for advanced-stage NSCLC patients treated with immunotherapy. This study included 52 advanced-stage NSCLC patients treated with Anti-PD1 or Anti-PD1 in combination with chemotherapy (Anti-PD1+CT) in the first line setting. Non-invasive biomarkers were analysed using peripheral blood samples, which were obtained before first cycle and at first response assessment. The potential biomarkers analysed in this study were: i) haematological and immunological parameters, ii) immune-related gene expression analysed on Peripheral Blood Mononuclear Cells (PBMCs), iii) TCR-ß repertoire, and iv) HLA genotype. 13 healthy subjects were also included in this study. NSCLC patients presented lower T cell related gene expression levels than controls. Furthermore, cancer patients had a lower number of unique TCR-ß clones. We have assessed the predictive and prognostic value of the analysed variables independently on patients treated with anti-PD1 or anti-PD1+CT. We found prognostic biomarkers that could be useful to identify patients who benefit from treatment. Since we used non-invasive samples, we also observed differences in immune-related biomarkers at first response assessment in patients responding to treatment. In addition, biomarker dynamics were useful to identify changes occurring throughout treatment. The integration of data from the analysed variables has resulted in a proposal of a multivariate model capable of predicting patients with improved outcomes to treatment with anti PD1 therapy. Moreover, we have developed two non-invasive inmunograms including the ratios of on- and pre-treatment samples, which could be useful to monitor patients throughout treatment. Altogether, this study highlights the role of non-invasive biomarkers to characterize and monitor immune status in NSCLC patients treated with immunotherapy or chemoimmunotherapy. / This Thesis was supported by the following grants: Fundación Científica Asociación Española Contra el Cáncer. PRDVA18015MORE; Centro de Investigación Biomédica en Red Cáncer. Project B16/12/00350 e Instituto de Salud Carlos III: PI18/00266 / Moreno Manuel, A. (2024). Non-Invasive Immunogram. A Multidimensional Approach to Characterize and Monitor Immune Status in Non-Small Cell Lung Cancer [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/204490

No description available.

Since its beginning, graft rejection remains the key problem of solid organ transplantation. This reaction of the recipient's immune system against mismatched antigens of the transplanted organ causes graft damage and consequently loss of its function. Rejection involves cellular (lymphocyte mediated) and humoral (antibody mediated) mechanisms. Among the genetic factors which may have a prognostic value in rejection risk evaluation are the Human Leukocyte Antigens (HLA) genotype, the Killer Immunoglobuline-like Receptor (KIR) gene repertoir, cytokine and other gene polymorphisms. These factors could be screened for before transplantation to find the best possible combination of genetic characteristics of the donor and recipient and to reveal patients with "risky" genotypes, who may need more intensive immunosuppression and more careful post-transplant follow-up. Molecular factors, such as HLA and non-HLA antibodies, soluble CD30 molecule (sCD30), Hepatocyte Growth Factor (HGF) and other cytokines, measured before and/or after transplantation in the recipient's blood may be helpful for rejection risk estimation and may also be used as post-transplant rejection onset markers. In our study, we focused on some of the above mentioned factors. We found that ethnicity plays a significant role in the...

Abstract Type 1 diabetes is considered to be a T cell-mediated autoimmune disease characterized by destruction of the pancreatic beta cells. Its prediction is currently based on diabetes-associated autoantibodies, giving a cumulative risk of 84% during 15 years of follow-up since seroconversion. Prediction of the timing of clinical onset has remained challenging, however. This thesis examines glucose metabolism in autoantibody-positive children with a high risk of developing type 1 diabetes. Out of a total of 14,876 children with an increased genetic risk followed up from birth in the Finnish DIPP study, 567 developed ≥2 autoantibodies during the follow-up and 255 of these (45%) were diagnosed with type 1 diabetes until the end of December 2011. The glucose parameters measured were HbA1c, OGTT and random plasma glucose with 3 to 12 months interval. Seven-day continuous glucose monitoring (CGM) was performed on an age and sex-matched cohort. We showed that rising HbA1c, impaired glucose tolerance in OGTT, random plasma glucose values of ≥7.8mmol/l and potentially CGM can predict type 1 diabetes with a median time to diagnosis of approximately one year. Our results suggest that especially HbA1c and random plasma glucose are cost-effective and improve the prediction of diabetes. These markers may be useful for monitoring the response to treatment in prevention studies. / Tiivistelmä Tyypin 1 diabetesta pidetään T-soluvälitteisenä autoimmuunitautina, joka johtaa haiman beetasolujen tuhoutumiseen. Tyypin 1 diabeteksen ennustaminen perustuu tällä hetkellä diabetekseen assosioituviin vasta-aineisiin, jotka antavat 84% kumulatiivisen riskin 15 vuoden seurannassa. Taudin puhkeamisen ajankohdan ennustaminen on kuitenkin edelleen vaikeaa. Tämä väitöskirja käsittelee glukoosiaineenvaihduntaa vasta-ainepositiivisilla lapsilla, joilla on suurentunut riski sairastua tyypin 1 diabetekseen. Suomalaisessa DIPP-tutkimuksessa vasta-aineiden kehittymistä on seurattu yhteensä 14876 lapselta. Seurannan aikana 567 lasta kehitti ≥2 autovasta-ainetta ja näistä 255 (45%) sairastui tyypin 1 diabetekseen joulukuun loppuun 2011 mennessä. Glukoosiaineenvaihduntaa seurattiin tutkimalla HbA1c, OGTT ja satunnaisia verensokeriarvoja 3-12 kuukauden välein. Ikä ja sukupuolivakioidussa kohortissa tehtiin jatkuvan sokeripitoisuuden seuranta (CGM). Tutkimuksessamme nouseva HbA1c, heikentynyt sokerin sieto OGTT-kokeessa, satunnainen verensokeri ≥7.8 mmol/l ja mahdollisesti CGM ennustavat tyypin 1 diabeteksen puhkeamista. Tulostemme perusteella erityisesti kustannustehokkaat HbA1c ja satunnainen verensokeri parantavat diabeteksen ennustamista. Nämä parametrit saattavat olla hyödyllisiä myös preventiotutkimuksissa hoitovasteen seurannassa.

We performed a retrospective study in 185 patients with myelogenous leukemias who had received hematopoietic cells from unrelated donors. The aim of this study was to answer the question wether the benefit of KIR ligand incompatibility seen in haploidentical tranplantations can also be seen using unrelated donors. We could not detect a significant difference in survival between patients with a KIR ligand incompatibility and those with either fully matched or partially mismatched unrelated donors in this patient cohort. / In der Therapie von Leukämien ist die Knochenmark- bzw. Stammzelltransplantation eine tragende Säule. Für den Transplantationserfolg ist eine Übereinstimmung der Haupthistokompatibilitätsantige (HLA-Antigene der Klassen I und II) zwischen Spender und Empfänger von zentraler Bedeutung. Diese Notwendigkeit ergibt sich aus der sogenannten MHC-Restriktion in der T-Zellrezeptorerkennung. Ob auch NK-Zellrezeptoren und deren Liganden in der Spenderauswahl berücksichtigt werden sollten, ist bisher unzureichend untersucht. Insbesondere trifft das für die KIR-Rezeptoren zu, die wie die T-Zellrezeptoren ebenfalls HLA-Antigene als Liganden besitzen. Velardi et al. haben 2002 erstmalig gezeigt, daß in der Therapie myeloischer Leukämien die Transplantation von Blutstammzellen verwandter Spender mit KIR-Liganden-Inkompatibilität von klinischem Vorteil ist. Ob KIR-Liganden-Inkompatibilität auch bei Knochenmark-/ Stammzelltransplantationen Unverwandter Bedeutung erlangen könnte, war zu Studienbeginn offen und blieb auch infolge diskrepanter Untersuchungsergebnisse von verschiedenen Arbeitsgruppen im Verlauf der Studie widersprüchlich. Im Rahmen dieser Arbeit wurde diese Fragestellung, die auch Teil einer internationalen Studie war, an 185 Spender-Empfänger-Paaren retrospektiv untersucht. Dabei wurde bei den Paaren einerseits die KIR-Liganden-Kompatibilität auf der Grundlage der HLA-C-Supertypen erschlossen (nach Velardi et al.). Andererseits konnte sie im internationalen Studienprogramm direkt aus dem KIR-Genotyp des Spenders und dem HLA-C-Supertyp des Empfängers ermittelt werden. Die Untersuchungen ergaben folgende Resultate: bei Vorliegen von KIR-Liganden-Inkompatibilität hat die Verwendung von ATG als Bestandteil der GvHD-Prophylaxe keinen Einfluß auf das klinische Ergebnis. Die Vermutungen von Giebel et al. wurden damit nicht gestützt. Die Bestimmung des KIR-Liganden-Status mit Hilfe der Rückschlußmethode allein aus dem HLA-Typ ist unzuverlässig. Für eine exakte Differenzierung ist die gleichzeitige KIR-Genotypisierung erforderlich. KIR-Liganden-Inkompatibilität ist bei unverwandten Knochenmark-/ Stammzelltransplantationen nicht von klinischem Vorteil. Auch ein gezieltes Aussuchen HLA-C-inkompatibler Spender auf der Grundlage einer KIR-Genotypisierung stellt derzeit keine therapeutische Option dar.